This invention relates generally to silver metachloridine compositions, and more particularly to the oral, systemic, or topical administration of that silver salt for the treatment or control of infections.
The existence of silver salts of p-aminobenzene sulfonamides and their chemotherapeutic activity are known. Relevant to chemotherapeutic effectiveness of such silver salts of sulfanilamide and congeners are U.S. Pat. Nos. 2,422,688; 3,761,590; and 4,020,150.
Compositions containing silver sulfadiazine have been shown to have broad microbiocidal effectiveness while being well tolerated by man and animals. Such compositions do also exhibit few untoward actions on the host while exerting desirable therapeutic effects. The stability of such compositions under a variety of conditions has been of marked consequence in their practical use. Applicant has determined that the silver salt of sulfadiazine is of unexpectedly complex character and appears to exist in two different forms, possibly of differing polymeric structures. Such structural features of that silver salt of a sulfanilamide derivative may well provide substantive basis for its profile of activity and lack of appreciable toxic effects, inclusive of argyrism.
The instant invention relates to the novel development of a microbiocidally effective silver salt of metachloridine which may be administered topically, orally, or systemically for treatment or control of various infections caused by diverse organisms, such as viruses, bacteria, fungi, or protozoa. It teaches a practical means for preparing the novel silver salt of metachloridine and methods for its use as a microbiocidal agent through evaluation under standardized laboratory tests which demonstrate its superiority over the silver salt of sulfadiazine.
The structures of sulfadiazine (I) and metachloridine (II) are hereinafter depicted. It is readily seen that (I) is chemically describable as 2-sulfanilaminidopyrimidine, and (II) is 5-chloro-2-metanilamidopyrimidine. Thus, although both compounds are relatable to a parent 2-aminopyrimidine, there are several clear differences in structure. Compound (I) is an N-2-pyrimidinyl derivative of sulfanilamide, which is 4-aminobenzenesulfonamide. Compound (II) is a derivative of metanilamide (3-aminobenzenesulfonamide) which further differs from (I) in the presence of a chlorine substituent (Cl grouping) at position 5 of the heterocyclic pyrimidine moiety. Each of the drugs (I) and (II) have been assessed in detail from the standpoint of microbiocidal effects and toxicological-pharmacological profiles in man as well as lower animals. ##STR1##
Practical utility of the silver salt of sulfadiazine has been demonstrated. In particular, the micronized drug has been incorporated into a water-miscible cream as an adjunct for the management of wounds, especially in prevention and treatment of sepsis in severe burns. A mode of action distinct from the silver salts and also sulfadiazine has been indicated for silver sulfadiazine, which has shown a low incidence of untoward effects in thousands of unselected cases. From laboratory studies, polymeric character has been indicated for both the silver salt of sulfadiazine and the herein described silver salt of metachloridine. In biological testing, the superiority of the novel product, silver metachloridine has been demonstrated over the previously known silver sulfadiazine. Allied 2-metanilamidopyrimidines, such as described by J. P. English, et. al. (J. Am. Chem. Soc., 68, 1039-1049 (1946), are also anticipated being useful in manufacture of congener silver salts having similar profiles of microbiocidal effectiveness and chemotherapeutic worth evident in the silver salt of metachloridine.
Regarding metachloridine, note must be taken that that particular sulfonamide itself, was the subject of considerable investigation during World War II. Under the designation SN-11 437, metachloridine was studied extensively as a candidate antimalarial agent: F. Y. Wiselogle, editor, "A Survey of Antimalarial Drugs, 1941-1945" (Edwards Brothers, Ann Arbor, Michigan, 1946), volumes I and II. SN-11 437 was sufficiently active in screening tests for antimalarial effects that it was given detailed chemotherapeutic and pharmacological evaluation. (loc. cit., volume I, pp. 294-299).